Alternative titles; symbols
HGNC Approved Gene Symbol: TLE6
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:2,977,401-2,995,179 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Oocyte/zygote/embryo maturation arrest 15 | 616814 | Autosomal recessive | 3 |
During mammalian follicular development, oocytes accumulate a substantial amount of maternal RNAs and proteins that are used by the early embryo prior to zygotic genome activation. Full-length TLE6 is a component of a subcortical maternal complex (SCMC) predicted to have a role in early embryonic development (Zhu et al., 2015).
Dang et al. (2001) cloned mouse Tle6, which they called Grg6. The deduced 581-amino acid protein shares significant similarity with the Drosophila groucho protein, particularly in the C-terminal WD40 repeat region. Northern blot analysis showed that Grg6 was expressed predominantly in heart, lung, liver, muscle, and testis, with very low expression in brain, spleen, and kidney.
Zhu et al. (2015) cloned 2 splice variants of TLE6 from human fetal ovary. Quantitative real-time RT-PCR detected full-length TLE6 expressed in ovary, with little to no expression in 8 other human tissues examined. The truncated form was detected almost exclusively in kidney. Confocal microscopy showed colocalization of NLRP5 (609658), KHDC3L (611687), OOEP (611689), and full-length TLE6 in the subcortex of oocytes and early embryos. After the 2-cell stage, all of the SCMC proteins migrated to regions away from cell-cell contact.
Hartz (2008) mapped the TLE6 gene to chromosome 19p13.3 based on an alignment of the TLE6 sequence (GenBank AK024071) with the genomic sequence (build 36.1).
Using representational difference analysis, Dang et al. (2001) found that the oncogenic E2A (TCF3; 147141)/HLF (142385) fusion protein upregulated expression of Grg6 and several other groucho-related genes following expression in a mouse pro-B cell line. A mutant E2A/HLF protein lacking DNA-binding activity also stimulated Grg6 expression.
Li et al. (2008) identified an SCMC in mouse that assembled during oocyte growth and was essential for zygotes to progress beyond the first embryonic cell division. Within this large complex, Floped (OOEP), Mater (NLRP5), and Tle6 interacted with each other, and Filia (see KHDC3L, 611687) independently bound Mater. Although the transcripts encoding these proteins were degraded during meiotic maturation and ovulation, the SCMC persisted in the early embryo. The SCMC, which was located in the subcortex of the egg, was excluded from regions of cell-cell contact in the cleavage-stage embryo and segregated to the outer cells of the morulae and blastocyst. Oocytes lacking Floped and/or Mater were fertilized, but the embryos did not progress beyond the cleavage stage of development, and female mice lacking Floped and/or Mater were sterile.
By reciprocal coimmunoprecipitation analysis of transfected HEK293T and HeLa cells, Zhu et al. (2015) demonstrated functional interaction between epitope-tagged KHDC3L, OOEP, NLRP5, and full-length TLE6. Truncated TLE6 did not interact with KHDC3L, OOEP, or NLRP5.
In 3 women from 2 consanguineous Saudi families with primary infertility due to preimplantation embryonic lethality (OZEMA15; 616814), Alazami et al. (2015) identified homozygosity for a missense mutation in the TLE6 gene (S510Y; 612399.0001). Functional analysis demonstrated that the mutation abrogates TLE6 phosphorylation by PKA (see 188830) and also impairs TLE6 binding to components of the SCMC.
Using Tle6-null mice, Yu et al. (2014) showed that Tle6 functioned as a critical maternal effect gene in early embryonic development. Tle6 stabilized the SCMC and was necessary for cleavage beyond the 2-cell stage of development. Mater, Filia, and Floped diffused from the SCMC in Tle6-null eggs. Loss of Tle6 resulted in uneven cell division and unequally sized blastomeres at the 2-cell stage. Zygotes from Tle6-null females lacked the F-actin meshwork found in control embryos and showed reduced concentration of subcortical F-actin and loss of phosphorylated cofilin (see 601442), a regulator of F-actin assembly required for symmetrical division of zygotes. Consequently, Tle6-null embryos died at the cleavage stage. Yu et al. (2014) concluded that TLE6 is required to stabilize the SCMC, which controls cofilin regulation of F-actin dynamics to ensure symmetric cell division in mouse zygotes.
In 3 women from 2 consanguineous Saudi families with primary infertility due to preimplantation embryonic lethality (OZEMA15; 616814), Alazami et al. (2015) identified homozygosity for a c.1529C-A transversion (c.1529C-A, NM_001143986.1) in the TLE6 gene, resulting in a ser510-to-tyr (S510Y) substitution at a highly conserved residue within a stretch of 7 WD40 domain repeats. The mutation was gender-specific, as a fertile brother in 1 of the families was also homozygous for S510Y. The mutation was found once in heterozygous state in 615 in-house Saudi exomes (allele frequency less than 0.001) and was not found in the 1000 Genomes Project and Exome Variant Server databases. In patient lymphoblastoid cells, phosphorylated TLE6 was reduced by more than 90% compared to controls. Immunoprecipitation and Western blot analysis using patient lymphoblastoid cells, as well as transfection experiments in HEK293 cells, showed reduced interaction between the S510Y mutant and 2 members of the human subcortical maternal complex, OOEP (611689) and KHDC3L (611687).
Alazami, A. M., Awad, S. M., Coskun, S., Al-Hassan, S., Hijazi, H., Abdulwahab, F. M., Poizat, C., Alkuraya, F. S. TLE6 mutation causes the earliest known human embryonic lethality. Genome Biol. 16: 240, 2015. Note: Electronic Article. [PubMed: 26537248] [Full Text: https://doi.org/10.1186/s13059-015-0792-0]
Dang, J., Inukai, T., Kurosawa, H., Goi, K., Inaba, T., Lenny, N. T., Downing, J. R., Stifani, S., Look, A. T. The E2A-HLF oncoprotein activates Groucho-related genes and suppresses Runx1. Molec. Cell. Biol. 21: 5935-5945, 2001. [PubMed: 11486032] [Full Text: https://doi.org/10.1128/MCB.21.17.5935-5945.2001]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/11/2008.
Li, L., Baibakov, B., Dean, J. A subcortical maternal complex essential for preimplantation mouse embryogenesis. Dev. Cell 15: 416-425, 2008. [PubMed: 18804437] [Full Text: https://doi.org/10.1016/j.devcel.2008.07.010]
Yu, X.-J., Yi, Z., Gao, Z., Qin, D., Zhai, Y., Chen, X., Ou-Yang, Y., Wang, Z.-B., Zheng, P., Zhu, M.-S., Wang, H., Sun, Q.-Y. Dean, J., Li, L. The subcortical maternal complex controls symmetric division of mouse zygotes by regulating F-actin dynamics. Nature Commun. 5: 4887, 2014. Note: Electronic Article. [PubMed: 25208553] [Full Text: https://doi.org/10.1038/ncomms5887]
Zhu, K., Yan, L., Zhang, X., Lu, X., Wang, T., Yan, J., Liu, X., Qiao, J., Li, L. Identification of a human subcortical maternal complex. Molec. Hum. Reprod. 21: 320-329, 2015. [PubMed: 25542835] [Full Text: https://doi.org/10.1093/molehr/gau116]